Multiple sclerosis (MS) is a complex and heterogeneous inflammatory disorder of the central nervous system (CNS) characterized by myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. MS is the most common cause of acquired neurological disability in the U.S. and European countries arising during early and mid-adulthood, and it affects more than one million people worldwide. The goal of this proposal is to identify genetic and non-genetic factors that predispose to MS and modulate phenotypic expression and/or progression. We describe for the first time in MS, a powerful approach to pursue strong and well-defined hypotheses critical to furthering our understanding of disease pathogenesis. We will investigate and refine the role of several promising candidate genes, the exposure to cigarette smoke and potential gene-environment interactions, and factors related to female reproductive history in MS susceptibility and disease modulation using a large, well characterized population-based case-control data set comprised of 3000 individuals. We will use well established strict ascertainment criteria and a suite of sophisticated tools including electronic database surveying, direct physician contact, chart review and comprehensive interviews to determine definite MS diagnoses and important phenotypic designations for this study. State of the art high-throughput genotyping methodologies and novel and comprehensive analytical approaches will be utilized. The complete elucidation of genetic and nongenetic influences underlying disease risk and heterogeneous MS phenotypes would clearly play a major role in understanding disease biology and would contribute significantly to disease prevention and the development of targeted and more effective therapeutics.